Information transmission in non-visual fingertip matching along a horizontal track in the median plane

Non-visually triggered arm movements over a horizontal table at shoulder height were analysed by an Information Theory approach according to a method suggested by Sakitt et al. (1983) and Sakitt (1980). The movement track was along the subject's median line and was indicated by a vertical metal ridge fixed to the table. The observer passively moved the subject's left index finger along the left side of the ridge to the target position. The blindfolded subject then had to move his right index finger along the right side of the ridge to match the left finger position. Direct contact between the two fingers was prevented by the ridge. We compared our results, which involve the transmission of information through the arm and shoulder joints of both arms, whith those of Sakitt et al. which involved just one elbow joint. We supplemented our experimental results with simulations and show that the value for the transmitted information, obtained using the method of analysis suggested by Sakitt et al., is very dependent upon the number of trials, and number and spacing of the targets. Sakitt et al. suggest that the Information Theory approach permits easy comparison between different tasks and different observers. Our results suggest that comparisons should be made with caution.     

Cholera Seasonality in Madras (1901–1940): Dual Role for Rainfall in Endemic and Epidemic Regions

The seasonality of cholera and its spatial variability remain unexplained. Uncovering the role of environmental drivers in these seasonal patterns is critical to understand temporal variability at longer time scales, including trends and interannual variability. Rainfall has been proposed as a key driver of the seasonality of cholera. To address this hypothesis, we examine the association between rainfall and cholera in both time and space using the extensive historical records for the districts of Madras in former British India (1901–1940). We show the existence of two main spatial clusters that differ not just in the effect of rainfall but also in the seasonal pattern and frequency of periods with and without cholera mortality. The results support a model of cholera seasonality with two different routes of transmission: one is enhanced by increasing rainfall (in areas with abundant water), the other is buffered by increasing water. We discuss how the dual nature of the influence of rainfall creates different temporal patterns in regions where cholera is either “endemic” or “epidemic.”     

Macrophage complement receptors and pathogen clearance

Phagocytosis, an important mechanism of the host-defence system and a primary function of macrophages, is facilitated by opsonization, a process by which serum components tag pathogens for recognition by neutrophils and macrophages. Complement component C3 is central to opsonization. Its first cleavage product, C3b, forms the multisubunit enzyme, C3bBb, which proteolytically cleaves additional C3 molecules on the pathogen surface. C3b is further degraded to iC3b, C3c and C3dg, products that serve as ligands for selective complement receptors on leukocytes. This receptor-ligand interaction subsequently modulates immune responses or directly targets the pathogen for clearance by phagocytosis. Although a central role for C3 in phagocytosis of certain pathogens is well accepted, the receptors orchestrating the phagocytic response have not been well characterized. The recent structures of C3 and its breakdown products have increased our insights into the molecular basis of complement activation and recognition by their receptors. Here we review the biology of macrophage receptors for C3 fragments and discuss their role in the host response to pathogens.     

Inhibiting alternative pathway complement activation by targeting the factor D exosite

By virtue of its amplifying property, the alternative complement pathway has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macromolecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of the substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 and 2.3 Å, respectively) revealed the molecular details of the inhibitory mechanism. The structures show that the AFD-binding site includes surface loops of FD that form part of the FD exosite. Thus, AFD inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway.     

Type 1 diabetes-associated HLA-DQ8 transdimer accommodates a unique peptide repertoire

HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). Yet HLA-DQ2/8 heterozygous individuals have a synergistically increased risk compared with HLA-DQ2 or HLA-DQ8 homozygote subjects that may result from the presence of a transdimer formed between the α-chain of HLA-DQ2 (DQA1*05:01) and the β-chain of HLA-DQ8 (DQB1*03:02). We generated cells exclusively expressing this transdimer (HLA-DQ8trans), characterized its peptide binding repertoire, and defined a unique transdimer-specific peptide binding motif that was found to be distinct from those of HLA-DQ2 and HLA-DQ8. This motif predicts an array of peptides of islet autoantigens as candidate T cell epitopes, many of which selectively bind to the HLA transdimer, whereas others bind to both HLA-DQ8 and transdimer with similar affinity. Our findings provide a molecular basis for the association between HLA-DQ transdimers and T1D and set the stage for rational testing of potential diabetogenic peptide epitopes.     

Opposite shell-coiling morphs of the tropical land snail Amphidromus martensi show no spatial-scale effects

Much can be learned about evolution from the identification of those factors maintaining polymorphisms in natural populations. One polymorphism that is only partially understood occurs in land snail species where individuals may coil clockwise or anti-clockwise. Theory shows that polymorphism in coiling direction should not persist yet species in several unrelated groups of land snails occur in stably polymorphic populations. A solution to this paradox may advance our understanding of evolution in general. Here, we examine two possible explanations: firstly, negative frequency-dependent selection due to predation; secondly, random fixation of alternative coiling morphs in tree-sized demes, giving the impression of wider polymorphism. We test these hypotheses by investigating morph-clustering of empty shells at two spatial scales in Amphidromus martensi populations in northern Borneo: the spatial structure of snail populations is relatively easy to estimate and this information may support one or other of the hypotheses under test. For the smaller scale we make novel use of a statistic previously used in botanical studies (the K-function statistic), which allows clustering of more than one morph to be simultaneously investigated at a range of scales and which we have corrected for anisotropy. We believe this method could be of more general use to ecologists. The results show that consistent clustering or separation of morphs cannot be clearly detected at any spatial scale and that predation is not frequency-dependent. Alternative explanations that do not require strong spatial structuring of the population may be needed, for instance ones involving a mechanism of selection actively maintaining the polymorphism.     

An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity

Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C > G: p.171P > R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C > G mutation causes an ～3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C > G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C > X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C > G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C > G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.     

Homology of a 130-kb region enclosing the α-globin gene cluster,the α-locus controlling region,and two non-globin genes in human and mouse

The human -globin gene cluster (30 kb) is embedded in a GC-rich isochore very close to the telomere of Chromosome (Chr) 16p. The -Locus Controlling Region (-LCR) is located upstream of the adult -globin genes and has been shown to be essential for their expression. In this study we have been looking for expressed genes in the region upstream of the -globin cluster to understand the role of the LCR-like element in the expression and replication timing of flanking gene clusters. We show that the upstream -globin region is conserved over a 75-kb range and includes at least two oppositely transcribed non-globin genes, here referred to as Mid1 and Dist1. Complementary DNA sequences of 250 bp and 2.5 kb from Mid1 (coordinate-68) and Dist1 (coordinate-90 to-99), respectively, were isolated from human and mouse. The deduced partial amino acid sequences of these cDNAs are 81% and 95% identical for the Mid1 and Dist1 gene respectively. We have cloned a mouse cosmid contig which includes Dist1, Mid1, and the entire murine -globin cluster. The murine homolog of the -LCR was mapped upstream of the mouse globin genes at approximately the same position as in the human locus. Our results indicate that, in mouse and human, the -globin loci and their flanking sequences are homologous over a range of at least 130 kb. The structural homology of this region in both mammals suggests also a functional one and indicates the mouse as a potential model for studying the role of the -LCR controlling element in the regulation of expression and replication timing of the flanking gene clusters.The nucleotide sequence data reported in this paper have been submitted to GenBank and have been assigned the accession numbers M99623, M99624, M99625, and M99626.